Mild Ring-Opening 1,3-Hydroborations of Non-Activated Cyclopropanes

Article abstract of DOI:10.1002/anie.201811036

The Brown hydroboration reaction, first reported in 1957, is the addition of B?H across an olefin in an anti-Markovnikov fashion. Here, we solved a long-standing problem on mild 1,3-hydroborations of non-activated cyclopropanes. A three-component system including cyclopropanes, boron halides, and hydrosilanes has been developed for borylative ring-opening of cyclopropanes following the anti-Markovnikov rule, under mild reaction conditions. Density functional theory (M06-2X) calculations show that the preferred pathway involves a cationic boron intermediate which is quenched by hydride transfer from the silane.

Full text of DOI:10.1002/anie.201811036

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Accepted Article
Title: Mild Ring-Opening 1,3-Hydroborations of Non-Activated
Cyclopropanes
Authors: Zhuangzhi Shi, Di Wang, Xiao-Song Xue, and Kendall Houk
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201811036
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10.1002/anie.201811036
Angewandte Chemie International Edition
C-C Borylation
C−N Bond Activation
Mild Ring-Opening 1,3-Hydroborations of Non-Activated Cyclopropanes
Di Wang, Xiao-Song Xue, Kendall N. Houk*, and Zhuangzhi Shi*
Abstract: The Brown hydroboration reaction, first reported in
1957, is the addition of B-H across an olefin in an anti-Markovnikov
fashion. Here, we solved a long standing problem on mild 1,3-
hydroborations of non-activated cyclopropanes. A three-component
system including cyclopropanes, boron halides and hydrosilanes has
been developed for borylative ring-opening of cyclopropanes
following anti-Markovnikov's rule under mild reaction conditions.
Density functional theory (M06-2X) calculations show that the
preferred pathway involves a cationic boron intermediate that is
quenched by hydride transfer from the silane.
Cyclopropanes are a fundamentally important class of compounds
not only because such small rings are found in many biologically
active compounds but also because a broad range of pharmaceutical
and agrochemical agents are synthesized from cyclopropanes, as
they can serve as useful synthetic building blocks.[1] The inherent
ring strain present in small rings is frequently used for ring-opening
reactions, many of which are not readily accessible by other
conventional methods.[2] Most of the existing cyclopropane ring-
opening approaches have relied on the specific functional group
assistance, including 1) polarizing one of the C–C bonds through the
attachment of an activated donor–acceptor cyclopropane,[3] and 2)
the attachment of directing groups that favour oxidative addition by
a transition metal to form metallacyclobutane intermediates (Figure
1a).[4] Although non-activated cyclopropanes are the most common
three-membered ring systems found in nature, methods for the
selective ring-opening of them remain scarce.[5] Some elegant
research works have recent demonstrated that they could undergo
1,3-addition of B(C6F5)3/tBu3P,[6] 1,3-aminofluorination,[7] 1,3-
difluorination,[8] 1,3-deoxygenation[9] and elimination[10] reactions.
Nevertheless, the development of new systems for efficient
opening/functionalization of these compounds under mild and
environmentally friendly conditions is still in high demand.
Figure 1. Ring-opening reactions of cyclopropanes
and alkenes,[17] we envisioned that the alkene-like π-donating
properties of non-activated cyclopropanes could take place the
similar electrophilic ring-opening and borylation. Herein, we
describe the discovery of a mild three-component system for the
ring-opening 1,3-hydroboration of non-activated cyclopropanes as
well as the simplest cyclopropane gas under a balloon pressure,
using BBr3 as a boron source and PhSiH3 as an external hydride
source (Figure 1c). Through mechanistic experiments and density
functional theory (DFT) calculations, we identified a stepwise
pathway for this transformation, which allows high reactivity at
room temperature.
Alkylboronic esters play important roles in a variety of fields
ranging from material science to drug discovery and organic
synthesis.[11] The well-known Brown hydroboration of olefins is a
classic transformation to synthesize them.[12] Hydroboration with
HBR2 (R = H, alkyl et al.) typically occurs in an anti-Markovnikov
manner. It proceeds via a four-membered concerted transition state:
the hydrogen and the boron atoms added on the same face of the
double bond (Figure 1b).[13] However, such a pathway for the
hydroboration of cyclopropanes is very sluggish.[14] High reaction
temperatures and poor functional group compatibility make this
transformation less practical. Because boron halides were known to
electrophilic borylation with arenes, heteroarenes,[15] alkynes[16]
We began our investigation by monitoring the reactivity of 2-(1-
methylcyclopropyl)naphthalene (1a) in the presence of boron Lewis
acids (Table 1). The reaction was found to be facile with 1.2
equivalents of BBr3 as a boron source in the presence of PhSiH3 as a
hydride source. In DCM at room temperature for 1 hour, 4,4,5,5-
tetramethyl-2-(3-(naphthalen-2-yl)butyl)-1,3,2-dioxaborolane (2a) is
formed in 92% GC yield after pinacol protection. PhSiH3 is crucial
for high conversion (entry 2). Inorganic reducing agents such as
NaBH4 and LiAlH4 and other hydrosilanes such as Et3SiH and
Ph2MeSiH were also effective and afforded boronate 2a in 48-63%
yields as the only ring-opened product (entries 3-6). The addition of
BCl3 also gave desired product 2a in 80% yield (entry 7), but BF3
did not work in this reaction (entry 8). Further exploration showed
that the common reagents applied in Brown hydroborations
(BH3·THF and HBBr2·Me2S) were completely ineffective in our
reaction, suggesting 2a is formed by a different pathway (entries 9
and 10).
[]
Di Wang, and Prof. Dr. Zhuangzhi Shi
State Key Laboratory of Coordination Chemistry, School of
Chemistry and Chemical Engineering, Nanjing University,
Nanjing 210093, China
With the optimal conditions in hand, we examined the scope of
this 1,3-hydroboration reaction (Table 2). Substrates containing
spiro cyclopropanes with an indane or tetralin scaffold (2b–c) were
all rapidly ring-opened, and the corresponding pinacol boronate
esters were isolated in excellent yields. Halogen substituents (F, Cl,
Br and I) work well under the reaction conditions (2d-h),
highlighting the potential of this process in combination with further
conventional cross-coupling transformations. While the O-
demethylation process with BBr3 is well documented, substrate 1i
bearing a methoxy group is compatible with this process, affording
E-mail: shiz@nju.edu.cn
Prof. Dr. Xiao-Song Xue, and Prof. Dr. Kendall N. Houk
Department of Chemistry and Biochemistry, University of
California, Los Angeles, California 90095, United States
E-mail: houk@chem.ucla.edu
Prof. Dr. Xiao-Song Xue
State Key Laboratory of Elemento-organic Chemistry, College
of Chemistry, Nankai University, Tianjin 300071, China
Supporting information and the ORCID identification
number(s) for the author(s) for this article can be found under
http://www.angewandte.org.
1
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10.1002/anie.201811036
Angewandte Chemie International Edition
desired product 2i in 55% yield. The reaction of 1,1-
diphenylcyclopropane (1j) in our system afforded desired
organic synthesis because it can be converted into other important
compounds by reactions such as Brown oxidation (9a), amination
Table 1. Reaction Optimization[a]
Table 2. Substrate Scope[a]
Yield of
Entry
Variation from the “standard conditions”
2a (%)[b]
1
2
none
92 (81)[c]
without PhSiH3
trace
48
55
52
63
80
0
3
NaBH4 instead of PhSiH3
LiAlH4 instead of PhSiH3
Et3SiH instead of PhSiH3
Ph2MeSiH instead of PhSiH3
BCl3 instead of BBr3
4
5
6
7
8
BF3∙Et2O instead of BBr3
BH3∙THF instead of BBr3 + PhSiH3
HBBr2∙Me2S instead of BBr3 + PhSiH3
9
0
10
0
[a] Conditions: All reactions were run at a 0.20-mmol scale in 1.0
mL of DCM at room temperature for 1 hour, and then pinacol (0.6
mmol) in Et3N was added, and the mixture was stirred for another 1
hour. [b] GC yield. [c] Isolated yield.
product 2j in 92% yield. Boronates 2k and 2l were obtained in good
yields from 1,1-arylalkylcyclopropanes after the ring-opening
reactions. 1,1-Dialkylcyclopropanes 1m-o could also be subjected to
our reaction conditions and desired products 2m-o were obtained in
good yields after the ring-opening/hydroboration reaction. Notably,
this reaction is not limited to cyclopropanes with a quaternary
carbon centre. Monosubstituted cyclopropanes 1p-v bearing aryl,
benzyl and alkyl groups worked well in this protocol and gave
corresponding products 2p-v with good yields and excellent
regioselectivity. Among these substrates, those containing Br (2s),
OPh (2t), SPh (2u) and carbazole (2v) functionalities were well
tolerated. Ring-opening and borylation of fused 1,2-disubstituted
cyclopropane 1w occurred most favourably at the secondary
methylene position, and ring expansion products were not observed.
Trans-1,2-alkylarylcyclopropane 1x was regioselectively converted
into 2x in 60% yield. However, cis-1,2-diphenylcyclopropane (1y)
was transformed into product 2y by cleavage of the most sterically
hindered σ bond. This mild hydroboration procedure can also be
utilized in late-stage functionalization of complexed biologically
active molecules. The investigation was started with the preparation
of cyclopropane 1z from estrone. Then, 1z was subjected to this
developed method to produce 2z in 56% isolated yields with good
diastereoselectivity.
[a] Reaction Conditions: 1 (0.50 mmol), BBr3 (0.60 mmol), PhSiH3 (0.60
mmol) in DCM (2.5 mL) at room temperature, 1 hour; then add pinacol (1.5
mmol) in Et3N was added, and the reaction was stirred for an additional 1
hour. [b] Using 1 (0.55 mmol), BBr3 (0.50 mmol). [c] Using 1 (0.50 mmol),
BBr3 (1.10 mmol). [d] Determined by crude 1H NMR.
The activation of small molecules has been an increasingly
popular area of research over recent years.[18] C-H borylation of
small molecules such as methane,[19] ethane[19a] and cyclopropanes[20]
have been developed recently. However, C-C bond
(9b), arylation (9c), heteroarylation (9d), and vinylation (9e)
reactions (For details, see supporting information).
cleavage/borylation of small molecules remains
a
major
challenge.[21] Having established optimal reaction conditions, we
found that the 1,3-hydroboration of cyclopropane gas (3) under the
n
pressure generated by a balloon could produce PrBpin (4) in 71%
yield (Scheme 1).
Compared to traditional Brown hydroborations of olefins, the
value of a 1,3-hydroboration of cyclopropanes is highlighted by the
fact that the corresponding product contains an additional methylene
substituent. As shown in Scheme 2, dehydroabietic acid (5) with a
carboxylic acid group readily produce olefin 6 and cyclopropane 7
in good yields. Not surprisingly, ring-opening of compound 7 on a
gram-scale results in boronate 8 with excellent yield. As noted at the
outset, the boronate group is an extremely versatile intermediate in
Scheme 1. 1,3-Hydroboration of Cyclopropane.
Several experiments were conducted to provide insight into the
potential mechanism of this transformation (Scheme 3). When the
reaction of 1a is conducted with PhSiD3 under standard reaction
conditions, the D label is nearly fully incorporated into 2a (84%
yield, 98% D). This observation confirmed that the hydrosilane is
2
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10.1002/anie.201811036
Angewandte Chemie International Edition
the sole source of the hydrogen atom in the product (Scheme 3a).
We further employed (R, R)-1x under the standard reaction
Figure 2. DFT-Computed Potential Energy Profile for the Model
Reaction Between Cyclopropylbenzene and BBr3 (standard state, 1
mol L-1).
Scheme 2. Derivatization of 1,3-Hydroboration Products.
conditions, and desired product (R)-2x was formed in 62% yield
with 58% ee. As the reaction temperature was gradually reduced, the
enantioselectivity of the product increased to 93% (Scheme 3b). To
further explore this process, PhSiD3 was added to the above reaction,
and the hydrogen on the chiral carbon was deuterated. Moreover, the
ratio of deuteration is consistent with the racemization product.
These results suggest that in situ-formed benzylic carbon cations
should be intermediates in these reactions and that 1,2-H migration
is likely to occur during the C–C cleavage process (Scheme 3c).
In conclusion, we have discovered a direct, catalyst-free method
for the 1,3-hydroboration of non-activated cyclopropanes under mild
reaction conditions. With the developed system in hand, the first
conversion of cyclopropane to n-propyl boronic esters has been
achieved. The reaction proceeds via a stepwise pathway through
energetically favourable transition states instead of a concerted four-
membered transition state. As a practical method, the reaction
cleanly and regioselectively produces widely used alkyl boronic
esters in good to excellent yields. Due to these advantages, this
reaction should be of high synthetic value.
Acknowledgments
The authors are grateful to the Chinese “Thousand Youth Talents
Plan” (for Z. S.), the “Innovation & Entrepreneurship Talents Plan”
of Jiangsu Province (for Z. S.) and the National Science Foundation
of the USA (CHE-1361104 to K.N.H.) for financial support.
Keywords: metal-free ·hydroboration ·cyclopropanes ·DFT ·C-C
activation
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Received: ((will be filled in by the editorial staff))
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10.1002/anie.201811036
Angewandte Chemie International Edition
Entry for the Table of Contents (Please choose one layout)
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C-C Borylation
Di Wang, Xiaosong Xue, Kendall N.
Houk*, and Zhuangzhi Shi*___ Page –
Page
Mild Ring-Opening 1,3-Hydroborations
of Non-Activated Cyclopropanes
CarBon A mild three-component system was developed for the preparation of
alkylboronic esters via ring-opening 1,3-hydroborations of non-activated
cyclopropanes. This method has good functional group compatibility and can serve
as a powerful synthetic tool for late-stage borylative ring-opening of cyclopropanes
in complex compounds.
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This article is protected by copyright. All rights reserved.